{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T07:20:57Z","timestamp":1787556057858,"version":"build-2736575974"},"reference-count":29,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T00:00:00Z","timestamp":1787443200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T00:00:00Z","timestamp":1787443200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100018904","name":"Beijing Xisike Clinical Oncology Research Foundation","doi-asserted-by":"publisher","award":["Y\u2010QLMS2025\u20100250"],"award-info":[{"award-number":["Y\u2010QLMS2025\u20100250"]}],"id":[{"id":"10.13039\/100018904","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FEBS Journal"],"abstract":"<jats:p>Hypoxia, a hallmark of the solid tumor microenvironment (TME), drives malignant progression and confers therapy resistance. In liver cancer, the hypoxia\u2010inducible factor\u20101\u03b1 (HIF\u20101\u03b1) has been implicated in suppressing ferroptosis, a key mechanism of therapy resistance; however, its precise regulatory network remains elusive. To systematically identify novel mediators within the HIF\u20101\u03b1\u2010ferroptosis axis, we integrated bioinformatic analyses of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets with experimental validation in hypoxic cells. This strategy identified ATG7 and KDM5C as core hypoxia\u2010responsive genes. ATG7, a key autophagy regulator, also maintains iron homeostasis and modulates oxidative stress, while the histone demethylase KDM5C regulates metabolic and antioxidant gene expression. To functionally dissect their roles, we engineered a novel dual\u2010fluorescence reporter system in HepG2 cells. This system utilizes a synthetic HIF\u20101\u03b1 responsive promoter, comprising five tandem repeats of the hypoxia response element (HRE), to drive EGFP expression, thereby reporting hypoxic signaling. Concurrently, the activity of the ATG7 or KDM5C promoter is reported by miRFP670. The resulting cell lines (HepG2\u2010ATG7p\u2010miRFP670\u20105HRE\u2010EGFP and HepG2\u2010KDM5Cp\u2010miRFP670\u20105HRE\u2010EGFP) thus visually couple promoter activity with the HIF\u20101\u03b1\u2010mediated hypoxic response. Our work provides a powerful visualizable platform to dynamically study the crosstalk between HIF\u20101\u03b1 and ferroptosis in liver cancer, facilitating the exploration of hypoxia\u2010ferroptosis interplay in hepatocarcinogenesis and therapeutic response.<\/jats:p>","DOI":"10.1111\/febs.70693","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T06:43:25Z","timestamp":1787553805000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>HIF<\/scp>\n                    \u20101\u03b1\u2010mediated regulation of\n                    <scp>ATG7<\/scp>\n                    and\n                    <scp>KDM5C<\/scp>\n                    in ferroptosis"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-9022-1339","authenticated-orcid":false,"given":"Kuoye","family":"Tian","sequence":"first","affiliation":[{"name":"School of Life Science and Technology, Xidian University and Engineering Research Center of Molecular and Neuro Imaging, Ministry of Education  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Chang","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, Xidian University and Engineering Research Center of Molecular and Neuro Imaging, Ministry of Education  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyu","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, Xidian University and Engineering Research Center of Molecular and Neuro Imaging, Ministry of Education  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dehong","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, Xidian University and Engineering Research Center of Molecular and Neuro Imaging, Ministry of Education  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5747-3349","authenticated-orcid":false,"given":"Yun","family":"Zeng","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, Xidian University and Engineering Research Center of Molecular and Neuro Imaging, Ministry of Education  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangyang","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology General Hospital of Ningxia Medical University  Yinchuan China"},{"name":"State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia Xinjiang Medical University  Urumqi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changhu","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology General Hospital of Ningxia Medical University  Yinchuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yonghua","family":"Zhan","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, Xidian University and Engineering Research Center of Molecular and Neuro Imaging, Ministry of Education  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5795-2366","authenticated-orcid":false,"given":"Wenhua","family":"Zhan","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology General Hospital of Ningxia Medical University  Yinchuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2295-3246","authenticated-orcid":false,"given":"Dan","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, Xidian University and Engineering Research Center of Molecular and Neuro Imaging, Ministry of Education  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,23]]},"reference":[{"key":"e_1_2_10_2_1","first-page":"7","article-title":"Cancer statistics, 2022","volume":"72","author":"Siegel RL","year":"2022","journal-title":"CA Cancer J Clin"},{"key":"e_1_2_10_3_1","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1038\/s41419-025-07772-0","article-title":"Targeting USP18 overcomes acquired resistance in hepatocellular carcinoma by regulating NCOA4 deISGylation and ferroptosis","volume":"16","author":"Ye S","year":"2025","journal-title":"Cell Death Dis"},{"key":"e_1_2_10_4_1","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1038\/s41419-023-06009-2","article-title":"Hexokinase 2 confers radio\u2010resistance in hepatocellular carcinoma by promoting autophagy\u2010dependent degradation of AIMP2","volume":"14","author":"Zheng Y","year":"2023","journal-title":"Cell Death 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opportunities and challenges","volume":"9","author":"Zhou X","year":"2022","journal-title":"Front Mol Biosci"},{"key":"e_1_2_10_9_1","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1038\/s41422-019-0263-3","article-title":"The role of ferroptosis in ionizing radiation\u2010induced cell death and tumor suppression","volume":"30","author":"Lei G","year":"2020","journal-title":"Cell Res"},{"key":"e_1_2_10_10_1","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1186\/s13045-020-00946-7","article-title":"Ferroptosis, necroptosis, and pyroptosis in anticancer immunity","volume":"13","author":"Tang R","year":"2020","journal-title":"J Hematol Oncol"},{"key":"e_1_2_10_11_1","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1002\/cac2.12250","article-title":"Ferroptosis in cancer and cancer immunotherapy","volume":"42","author":"Zhao L","year":"2022","journal-title":"Cancer 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